1. Field of the Invention
This invention relates to an improved process for the acylation of aromatic compounds utilizing boron trifluoride as a catalyst and liquid sulfur dioxide as a solvent.
2. Description of Related Art
Aromatic ketones are valuable intermediates useful in the production of pharmaceutical compounds, cosmetics and in other applications.
For example, U.S. Pat. No. 4,607,125 discloses that hydroxy aromatic ketones, such as 4-hydroxyacetophenone, are useful in the production of N-acyl-p-aminophenol, better known as acetaminophen which has wide use as an analgesic. Acylation is accomplished by reacting phenol with an acylating agent such as acetic anhydride in the presence of a Friedel-Crafts type catalyst such as aluminum chloride, hydrogen fluoride (HF) or boron trifluoride (BF.sub.3). HF is preferred because it also serves as a solvent medium for the reaction.
U.K. Patent publication 2102420A teaches the preparation of aromatic diaryl ketones by reacting a substituted benzene with an aromatic acyl compound in the presence of a mixture of a Lewis acid which may include BF.sub.3 and a strong acid which may include HF. The reaction medium may also include a polar solvent such as sulfur dioxide, tetramethylene sulfone, nitrobenzene and similar materials.
U.S. Pat. No. 4,454,350 discloses the preparation of p-haloacetophenones which are useful as intermediates in the preparation of pharmaceutical compounds and herbicides wherein starting materials such as fluorobenzene are reacted with an acylating agent such as acetic anhydride or acetyl chloride in a mixed system comprising HF as a solvent and BF.sub.3 as a catalyst.
European Patent Publication EP-199661-A teaches the acylation of biphenyl to produce 4-acetyl biphenyl or 4,4,-diacetyl biphenyl using an acetylating compound such as acetic anhydride and using HF, or a mixture of HF and CH.sub.2 Cl.sub.2 as solvents, and BF.sub.3 as the reaction catalyst.
U.S. Pat. No. 4,474,990 discloses a similar process for the preparation of p-phenoxybenzoyl compounds, which are useful in the production of polyetherketone resins, by acylation of diphenyl ether using an acylating compound such as acetic anhydride and HF as a catalyst and diluent. The reference indicates on the top of column 3 that the reaction media may also include an optional diluent such as alkanes, haloalkanes, sulfur dioxide and similar materials.
Ibuprofen [2-(4'-isobutylphenyl)propionic acid] is a well-known nonsteroidal anti-inflammatory pharmaceutical which has been converted from ethical, i.e., prescription, to over-the-counter status. It is generally prepared by the catalytic acetylation of isobutyl benzene (IBB) with a suitable acetylation compound such as acetic anhydride to form 4-isobutylacetophenone (IBAP). The reduction (catalytic hydrogenation) of IBAP leads to 1-(4'-isobutylphenyl) ethanol (IBPE); carbonylation of IBPE yields Ibuprofen.
The preparation of 4-isobutylacetophenone from isobutylbenzene is known in the art. For example, Braddely et al., Journal of the American Chemical Society, 4943-4945 (1956), discloses on p. 4945 the preparation of 4-isobutylacetophenone by the Friedel-Crafts acetylation of isobutylbenzene with acetyl chloride using aluminum chloride as a catalyst.
In addition, Japanese Patent Publication no. 60 [1985]-188343 discloses the preparation of 4-isobutylacetophenone by the acetylation of isobutylbenzene using acetyl fluoride as an acetylating agent, which is prepared by reacting acetic anhydride with HF as a catalyst, or a combination of HF and BF.sub.3 as catalysts.
Commonly assigned copending application Docket Number N-7043C discloses a process for acetylating isobutylbenzene using an appropriate acetylating agent such as acetic anhydride and in the presence of HF which serves as a catalyst and solvent.
While all of the above and other acylation processes are effective to varying degrees, they suffer certain deficiencies, particularly when scaled up for commercial production. For example, conventional Friedel Crafts catalysts such as aluminum chloride either can not be recycled or are recycled with difficulty from the reaction mass. In addition, HF is a highly protic solvent and the separation of HF from an HF/BF.sub.3 /aromatic ketone reaction product must be accomplished rapidly in order to avoid decomposition of the aromatic ketone reaction product. This would require the utilization of a reactor distillation column to effect this separation. Yet a third factor is the percent conversion of the aromatic starting material to the desired ketone and the selectivity of the process for producing the desired ketone as compared with its isomers. Conversion and selectivity are largely a function of the specific catalyst and the solvent employed in the process. For example, in the commercial process for preparing 4-isobutylacetophenone from isobutylbenzene using acetic anhydride as an acetylating agent and HF as a catalyst, the reaction generally proceeds with less than 90% conversion of the isobutylbenzene starting material and less than 85% selectivity toward production of the desired 4-isomer vs. other isomers such as the 3-isomer or 3,4-isomer combination.
Such drawbacks result in production inefficiencies due to the requirement for additional separation and/or purification steps in the production process, as well as equipment for accomplishing these steps, and lower yields of the desired product.
Acylation of aromatic compounds using an aluminum halide catalyst and a solvent medium other than HF have been described in the prior art. For example, U.S. Pat. No. 2,245,721 discloses the acylation of aromatic compounds by reaction with carboxylic acid halides or anhydrides in the presence of an aluminum halide catalyst and liquid sulfur dioxide as a solvent. Although the patent describes numerous advantages which inure as the result of using sulfur dioxide in the process, the yield of reaction product is extremely low, e.g., a 45% yield of acetophenone from benzene and acetyl chloride using an aluminum chloride catalyst as indicated in Example 3 of the patent. Also, as pointed out above, the aluminum chloride catalyst can not be recycled for further use as is desirable in a commercial scale process.
Accordingly, it is an object of this invention to provide an efficient and economical process for preparing aromatic ketones.
Another object of this invention is to provide a process for acylating aromatic compounds without the need to use highly protonic solvents.
Another object is to provide a process for preparing 4-isobutylacetophenone wherein a high conversion of the isobutylbenzene starting material is realized.
Yet another object is to provide an acetylation process which is highly selective towards the production of 4-isobutylacetophenone in contrast to its related isomers.